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How does pyruvate dehydrogenase deficiency cause lactic acidosis?

How does pyruvate dehydrogenase deficiency cause lactic acidosis?

As with PDHA1 gene mutations, changes in these other genes lead to a reduction of pyruvate dehydrogenase complex activity. With decreased function of this complex, pyruvate builds up and is converted in another chemical reaction to lactic acid. The excess lactic acid causes lactic acidosis in affected individuals.

How is PDCD diagnosed?

A definitive clinical diagnosis can be made by measuring abnormal PDC enzyme levels or function in leukocytes, fibroblasts or from a tissue biopsy. Genetic diagnosis can be made by the identification of pathogenic variants in the PDHA1, PDHX, PDHB, DLAT, PDP1 or DLD genes.

What happens if pyruvate dehydrogenase doesn’t work?

When the pyruvate dehydrogenase complex is not working properly, pyruvate can’t be converted to acetyl-CoA. This causes pyruvate to build up in cells. The pyruvate instead is turned into lactic acid, which is toxic to the body in large amounts and causes lactic acidosis.

Why does a deficiency in PDHC activity cause lactic acidosis?

The oxidative metabolism of pyruvate, the end product of glycolysis, proceeds through PDHC into the TCA cycle and the mitochondrial respiratory chain. A deficiency of any enzyme in these pathways results in inadequate removal of pyruvate and lactate from blood and tissues and causes lactic acidosis.

Is pyruvate dehydrogenase deficiency fatal?

Pyruvate dehydrogenase deficiency (PDHD) is a rare neurometabolic disorder characterized by a wide range of clinical signs with metabolic and neurological components of varying severity. Manifestations range from often fatal, severe, neonatal lactic acidosis to later-onset neurological disorders.

How is PDH deficiency treated?

Treatment is generally aimed at stimulating the PDH complex or providing an alternative energy source for the brain. Cofactor supplementation with thiamine, carnitine, and lipoic acid has been recommended. A very small number of patients with mutations in the PDHA1 gene are thiamine-responsive.

What stimulates the pyruvate dehydrogenase complex?

Both of these regulatory enzymes are regulated. PDH kinase is stimulated by NADH and acetyl-CoA. It is inhibited by pyruvate. PDH phosphatase is stimulated by Ca++ and insulin.

Who is at risk for pyruvate dehydrogenase complex deficiency?

Pyruvate dehydrogenase complex (PDC) deficiency is suspected in people who have lactic acidosis or signs of early-onset neurological disease such as seizures, lethargy, and poor feeding. A doctor may wish to order more tests including: [1]

What happens when pyruvate is not converted into acetyl-CoA?

The pyruvate instead is turned into lactic acid, which is toxic to the body in large amounts and causes lactic acidosis. When pyruvate isn’t converted into acetyl-CoA, the body also can’t go through the citric acid cycle.

What are the symptoms of lactic acidosis in babies?

Some babies with severe lactic acidosis may have high levels of ammonia in the blood (hyperammonemia). Other symptoms of PDC deficiency can include having low muscle tone ( hypotonia ), poor feeding, extreme tiredness (lethargy), rapid breathing ( tachypnea ), abnormal eye movements, and seizures.

What are the physical features of PDC deficiency?

Some features that may be characteristic of PDC deficiency include a narrow head, prominent forehead ( frontal bossing ), wide nasal bridge, long philtrum, and flared nostrils. However, these features are not present in all babies with PDC deficiency.